This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Herpesviruses are human pathogens that infect their hosts for life, causing cold sores, genital herpes, blindness, encephalitis, cancers, and life-threatening conditions in immuno-compromised individuals. The goal of our research is to understand in atomic-level detail how herpesviruses enter host cells. Such information will be invaluable in designing anti-herpesvirus therapeutics to combat both viral infections and cell-cell spread. The herpesvirus cell-entry mechanism is very complex. Whereas other enveloped viruses use a single protein to effect cell entry, all herpesviruses require at least three proteins: gB, gH, and gL. These three proteins are thought to accomplish the fusion of viral and cell membranes [unreadable]a pivotal step in viral entry [unreadable]but their exact functions are obscure. We aim to determine how gB and gH/gL proteins of Herpes Simplex Virus (HSV) work together to accomplish membrane fusion and how the signal from the receptor-binding protein, gD, triggers the membrane-fusion machinery. Uncovering how these proteins work in HSV infection will also reveal their functions in other herpesviruses because the membrane-fusion machinery, i.e., gB, gH, and gL, is highly conserved.